Aldosterone Antagonism in Heart Failure: Now for all Patients?

Transcription

1 Aldosterone Antagonism in Heart Failure: Now for all Patients? Inder Anand, MD, FRCP, D Phil (Oxon.) Professor of Medicine, University of Minnesota, Director Heart Failure Program, VA Medical Center 111C Minneapolis, USA

2 Presenter Disclosure Information I will not discuss off label use and/or investigational use in my presentation. I have financial relationships to disclose: Consultant: Amgen, Corventis, CVRx, Medtronic, Paracor, Sanofi- Aventis Research Grants: Amgen, BG Medicine, Corventis, Novartis, Paracor

3 Aldosterone

4 Effects of Aldosterone Released from adrenal cortex in response to angiotensin II, ACTH, and K + Na + & water retention Increases Cardiac fibrosis Increases cardiac norepinephrine K + & Mg + loss Increases PAI-1 Endothelial dysfunction Decreases vascular compliance CHF Sudden Death Atherosclerosis: CAD, Stroke, MI, CRF

5 Aldosterone levels are Increased in Heart Failure Val-HeFT Trial Aldosterone levels were available in 4,048 of 5,010 randomized patients at baseline Mean (±SD) baseline aldosterone ± 143 pg/ml (median pg/ml) Anand et al 2003 Circulation

6 Baseline characteristics of all randomized patients dichotomized by aldosterone levels Variable Aldosterone Aldosterone P - value <104.1 pg/ml >104.1 pg/ml NYHA III /IV, (%) <0.001 SBP, mmhg <0.001 HR, b/min <0.001 LVEF, % <0.001 MLWHF*, overall score <0.001 Mean plasma Aldo, pg/ml <0.001 Mean plasma BNP, pg/ml Mean Plasma, NE pg/ml <0.001 Mean PRA, ng/ml/hr <0.001 Anand et al 2003 Circulation

7 Baseline aldosterone and outcomes in Val-HeFT Aldosterone as a continuous variable Significant determinant of both all cause mortality and first morbid event Anand et al 2003 Circulation

8 Proportion survived Proportion w/o first morbid event K-M curves - mortality and first morbid event Aldosterone above vs below median All-cause mortality < > First morbid event < > p = (log-rank) 0.6 p = (log-rank) Time since randomization (months) Anand et al 2003 Circulation

9 Spironolactone Effectively Blocks the Mineralocorticoid Receptors

10 RALES-I (Randomized Aldactone Evaluation Study) Randomized, dose-finding study, to determine dosing strategy & safety of spironolactone used with an ACE-I & diuretic in patients with CHF. Patients: NYHA class II to III pts with previous h/o class IV symptoms, EF<35%. All on ACE-I & diuretics and 78% on digoxin. Patients were randomized to placebo or spironolactone 12.5, 25, 50, or 75 mg QD. Assessment: - 12 weeks later for changes in clinical status, serum Cr, serum K, PRA, ANP, & aldosterone excretion. (The RALES investigators Am J Cardiol 1996;78:902-7)

11 RALES - I RESULTS After 12 weeks no difference in NYHA class in the two groups. Spironolactone caused a dose-dependent decrease in body weight, BP, ANP, and increase in serum K, serum Cr, PRA & urinary aldosterone excretion. (The RALES investigators Am J Cardiol 1996;78:902-7)

12 Plasma ANP (pmpl/l) Plasma ANP (pmol/l) Plasma ANP (pmol/l) RALES - I (Change in Plasma ANP) Placebo 12.5 mg 25 mg 50 mg 75 mg Spironolactone (The RALES investigators Am J Cardiol 1996;78:902-7)

13 Change in Serum Potassium (mmol/l) Change in Serum Potassium (mmol/l) Change in Serum Potassium (mmol/l) RALES - I (Change in Serum Potassium) Placebo 12.5 mg 25 mg 50 mg 75 mg Spironolactone (The RALES investigators Am J Cardiol 1996;78:902-7)

14 Incidence of Hyperkalemia (%) Incidence of Hyperkalemia (%) Incidence of Hyperkalemia (%) RALES - I (Incidence of Serum Potassium > 5.5 mmol/l) % 24 % % 5 5 % 5 % 0 Placebo 12.5 mg 25 mg 50 mg 75 mg Spironolactone (The RALES investigators Am J Cardiol 1996;78:902-7)

15 RALES - I Conclusion Daily doses of 12.5 to 25 mg of spironolactone administered with conventional doses of ACE-I, loop diuretics, and digoxin are relatively safe and effective in blocking the effects of aldosterone, with development of relatively mild hyperkalemia in patients with CHF. (The RALES investigators Am J Cardiol 1996;78:902-7)

16 RALES Trial (Randomized Aldactone Evaluation Study) 1663 patients with severe heart failure LV ejection fraction 35% Receiving ACE-I, loop diuretic, and digoxin Exclusion: Cr> 2.5, K>5.0 Randomized to spironolactone 25 mg QD (n=822) or placebo (841) Labs at 1 and 4 weeks Drug held for K >6.0 or Cr >4.0 Primary endpoint: All-cause mortality Several secondary endpoints Pitt B et al., N Eng J Med 1999; 341:

17 Probability of survival RALES Trial All-Cause Mortality Randomization: 70% NYHA class III; 30% class IV Mean EF 25%, 95% on ACE-I; 10% BB Results: Trial stopped > 1 year prematurely Mean follow-up 24 months HR 0.70 ( ) Spironolactone 35% Annual mortality in placebo group 27% 30% reduction in all-cause mortality 35% reduction in worsening HF Reduction in all secondary endpoints Gynecomastia in 10% P<0.001 Placebo 46% Months Pitt B et al. New Engl J Med 1999;341:

18 The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure Treatment with spironolactone reduced the risk of: Death from all causes Death from cardiac causes Hospitalizations from cardiac causes Combined death or hospitalizations from cardiac causes Improved the symptoms of heart failure Pitt B et al., N Eng J Med 1999; 341:

19 EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy SUrvival Study) Double-blind, placebo-controlled trial of the effects of eplerenone on morbidity and mortality in patients with acute MI, complicated by LV dysfunction and heart failure 6642 patients within 3 to 14 days of AMI, LVEF < 40% and HF (Rales, PV congestion on CXR or S 3 ) or diabetes with no HF were randomized to placebo (3319) or eplerenone (n=3313, 25 mg QD, titrated to max of 50 mg QD). Two Primary end points: All-cause Mortality Cardiovascular death or CV hospitalization (heart failure, MI, stroke, or ventricular arrhythmia) Pitt B. et al., N Engl J Med 2003; 348:

20 Cumulative Incidence (%) EHPHESUS All Cause Mortality Eplerenone 3 to 14 days after MI 40 15% all-cause mortality 13% CV mortality & CV hosp. 17% CV mortality 21% Sudden death 23% HF hospitalizations RR=0.85 (95% CI, ), P=0.008 Placebo Eplerenone Months Since Randomization Pitt B. et al., N Engl J Med 2003; 348:

21 Adverse Events Adverse Events Eplerenone (N=3307) Placebo (N=3301) P Value Disorder of skin or appendages 220 (6.7) 223 (6.8) 0.88 Musculoskeletal disorder 209 (6.3) 213 (6.5) 0.84 Nervous system disorder 492 (14.9) 449 (13.6) 0.14 Psychiatric disorder 238 (7.2) 272 (8.2) 0.12 Gastrointestinal disorder 659 (19.9) 583 (17.7) 0.02 Endocrine disorder 34 (1.0) 23 (0.7) 0.18 Disorder in men 59 (2.5) 65 (2.8) 0.53 Gynecomastia 12 (0.5) 14 (0.6) 0.70 Impotence 21 (0.9) 20 (0.9) 1.00 Disorder in women 17 (1.8) 17 (1.7) 1.00 Breast pain 1 (0.1) 3 (0.3) 0.63 Serious hyperkalemia (K+ >6.0mm/L) 180 (5.5) 126 (3.9) Serious hypokalemia (K+ <3.5mm/L) 273 (8.4) 424 (13.1) <0.001 Pitt B. et al., N Engl J Med 2003; 348:

22 EPHESUS Conclusions Addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute MI complicated by LV dysfunction and heart failure Pitt B. et al., N Engl J Med 2003; 348:

23 LV End diastolic vol. (ml/m 2 ) LV End diastolic vol. (ml/m 2 ) Spironolactone Attenuates LV Remodeling Early and late after MI Spironolactone Placebo P = ns P< P<0.05 P< Baseline 1 month 40 Baseline 6 month 12 month Hayashi M, et al, Circulation. 2003; 107: Modena et al. Am Heart J 2001; 141: 41-6

24 HFSA 2010 Practice Guideline ( ) Aldosterone Antagonists 1. An aldosterone antagonist is recommended for patients on standard therapy, including diuretics, who have NYHA class IV HF (or class III, previously class IV) due to LV systolic dysfunction (LVEF 35%). Class I, Level of Evidence = A 2. It should be considered in patients post-mi with clinical HF or diabetes and an LVEF < 40% who are on standard therapy. Class IIa; Level of Evidence = A Lindenfeld J, et al HFSA 2010 Guidelines J Cardiac Failure 2010;16:e1-e199.

25 HFSA 2010 Practice Guideline ( ) Aldosterone Antagonists and Renal Function Aldosterone antagonists are not recommended when: Creatinine > 2.5mg/dL (or clearance < 30 ml/min) Serum potassium> 5.0 mmol/l When therapy includes other potassium-sparing diuretics Class III, level of Evidence = A It is recommended that potassium be measured at baseline, then 1 week, 1 month, and every 3 months Class I, level of Evidence = A Supplemental potassium is not recommended unless potassium is < 4.0 mmol/l Class I, level of Evidence = A Lindenfeld J, et al HFSA 2010 Guidelines J Cardiac Failure 2010;16:e1-e199.

26 EMPHASIS-HF Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure

27 EMPHASIS-HF Hypothesis: Aldosterone antagonism with eplerenone will be of benefit in patients with LV systolic dysfunction and mild HF symptoms Population: 2737 patients 60 yrs, NYHA II HF, LVEF 30% (or LVEF 31-35% and QRS >130 msec.) CV hospitalization within 6-months (or BNP 250 pg/ml or NT-proBNP 500 pg/ml in men/ 750 pg/ml in women. Exclusion criteria: NYHA class III and IV, K + >5.0 mmol/l, egfr <30 ml/min Randomization: Eplerenone (25 to 50 mg) vs Placebo Primary endpoint: Composite of CV death or HF hospitalization event driven (813 events)

28 EMPHASIS-HF: Baseline characteristics (1) Characteristic Eplerenone (n=1364) Placebo (n=1373) Age - yr Male (%) Heart rate beats/min Systolic blood pressure mmhg LVEF (%) QRS duration -msec Duration of heart failure yr 5 5 Medical history (%) Hospitalization for heart failure Hypertension Myocardial infarction 50 51

29 EMPHASIS-HF: Baseline characteristics (2) Eplerenone (n=1364) Placebo (n=1373) Medical history continued (%) Atrial fibrillation or flutter LBBB in nonpaced baseline ECG Diabetes mellitus Medication (%) ACE inhibitor, ARB or both Beta-blocker Digitalis glycoside 27 28

30 EMPHASIS-HF Primary outcome CV Death or HF Hospitalization Results: Trial stopped prematurely after a mean follow-up 21 months 25.9% 37% reduction in Primary endpoint 24% reduction in all-cause mortality 18.3% 42% reduction in hospitalization for HF 19 patients needed to be treated for 1-year to prevent on Primary outcome Zannad F, et al. NEJM 2010;364:11-21.

31 EMPHASIS-HF Primary Endpoint in all Patients and in All High Risk Subgroups Pitt et al ESC Congress, Paris, September 2011

32 Comparison of Major Mineralocorticoid Receptors Antagonist Trials

33 The missing piece of the aldosteroneantagonist jigsaw LVSD and HF/ diabetes after AMI Mild HF symptoms (NYHA class II) Severe HF symptoms (NYHA class III/IV) EPHESUS EMPHASIS-HF RALES

34 Are we Changing our Practice?

35

36 What effect will EMPHASIS-HF have on clinical practice? NYHA class II % Percent Patients

37 Hyperkalemia with Spironolactone Real Life HF Therapy Canada Spironolactone Prescription Rate Before and After Publication of RALES Juurlink et al NEJM 2004

38 Hyperkalemia with Spironolactone Real Life HF Therapy Canada In-hospital Death from Hyperkalemia Before and After Publication of RALES Juurlink et al NEJM 2004

39 Can We Explain the Juurlink Data? Renal dysfunction was more frequent Serum creatinine levels 1.8 to 20 mg/dl c/t 1.2 mg/dl in RALES Doses of spironolactone higher than RALES Many patients took potassium supplements Follow-up was less vigorous than in clinical trials

40 Findings of a British

41 RAAS Blockade and Hyperkalemia How Frequent? How to Predict it? How to Prevent it? How to Manage it?

42 Incidence of Hyperkalemia

43 RAAS Blockade and Hyperkalemia

44 RAAS Blockade and Hyperkalemia

45 How to Predict it? Risk Factors for Hyperkalemia 3 independent risk factors have been identified Baseline K + Baseline Creatinine clearance (egfr) History of diabetes None of above associated with differential treatment effect for outcomes

46 EMPHASIS-HF Primary Endpoint in all Patients and in All High Risk Subgroups Pitt et al ESC Congress, Paris, September 2011

47 RAAS Blockade and Hyperkalemia

48 RAAS Blockade and Hyperkalemia Approach to Patients at Risk for Hyperkalemia by RAAS Blockade Estimate egfr Use low dose drug if egfr <60 ml/min/1.73m 2 Do not use drug if egfr <30 ml/min/1.73m 2 Discontinue drugs that interfere with K + secretion NSAIDs, Selective COX2 inhibitors, Herbal preparations Prescribe low K + diet, stop salt substitutes that contain K + Prescribe thiazide or loop diuretics (loop diuretics necessary when egfr <30 ml/min/1.73 m 2.

49 How to Manage it? Do not initiate aldosterone blocker if K + >5.0 mmol/l Measure K + 1-week, 1-month and then every 4-months after initiation of aldosterone blocker Reduce dose by half if K + is 5.5 to 5.9 mmol/l Withhold drug if K + >6.0 mmol/l Remeasure K + within 72-hours after dose reduction or drug withdrawal Restart drug only if K + < 5.0 mmol/l

50 RAAS Blockade and Hyperkalemia CONCLUSIONS The fear of inducing hyperkalemia should not limit the initiation of ACE-I, ARB, or aldosterone blockers in patients with HF The risk of hyperkalemia is mainly driven by worsening renal function Hyperkalemia is predictable, preventable and manageable Beneficial effects of RAAS blockade override adverse effects